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Genetic modifiers of radon-induced lung cancer risk: a genome-wide interaction study in former uranium miners.

ABSTRACT: PURPOSE:Radon is a risk factor for lung cancer and uranium miners are more exposed than the general population. A genome-wide interaction analysis was carried out to identify genomic loci, genes or gene sets that modify the susceptibility to lung cancer given occupational exposure to the radioactive gas radon. METHODS:Samples from 28 studies provided by the International Lung Cancer Consortium were pooled with samples of former uranium miners collected by the German Federal Office of Radiation Protection. In total, 15,077 cases and 13,522 controls, all of European ancestries, comprising 463 uranium miners were compared. The DNA of all participants was genotyped with the OncoArray. We fitted single-marker and in multi-marker models and performed an exploratory gene-set analysis to detect cumulative enrichment of significance in sets of genes. RESULTS:We discovered a genome-wide significant interaction of the marker rs12440014 within the gene CHRNB4 (OR?=?0.26, 95% CI 0.11-0.60, p?=?0.0386 corrected for multiple testing). At least suggestive significant interaction of linkage disequilibrium blocks was observed at the chromosomal regions 18q21.23 (p?=?1.2?×?10-6), 5q23.2 (p?=?2.5?×?10-6), 1q21.3 (p?=?3.2?×?10-6), 10p13 (p?=?1.3?×?10-5) and 12p12.1 (p?=?7.1?×?10-5). Genes belonging to the Gene Ontology term "DNA dealkylation involved in DNA repair" (GO:0006307; p?=?0.0139) or the gene family HGNC:476 "microRNAs" (p?=?0.0159) were enriched with LD-blockwise significance. CONCLUSION:The well-established association of the genomic region 15q25 to lung cancer might be influenced by exposure to radon among uranium miners. Furthermore, lung cancer susceptibility is related to the functional capability of DNA damage signaling via ubiquitination processes and repair of radiation-induced double-strand breaks by the single-strand annealing mechanism.

SUBMITTER: Rosenberger A

PROVIDER: S-EPMC6375683 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Genetic modifiers of radon-induced lung cancer risk: a genome-wide interaction study in former uranium miners.

Rosenberger Albert A Hung Rayjean J RJ Christiani David C DC Caporaso Neil E NE Liu Geoffrey G Bojesen Stig E SE Le Marchand Loic L Haiman Ch A CA Albanes Demetrios D Aldrich Melinda C MC Tardon Adonina A Fernández-Tardón G G Rennert Gad G Field John K JK Kiemeney B B Lazarus Philip P Haugen Aage A Zienolddiny Shanbeh S Lam Stephen S Schabath Matthew B MB Andrew Angeline S AS Brunnsstöm Hans H Goodman Gary E GE Doherty Jennifer A JA Chen Chu C Teare M Dawn MD Wichmann H-Erich HE Manz Judith J Risch Angela A Muley Thomas R TR Johansson Mikael M Brennan Paul P Landi Maria Teresa MT Amos Christopher I CI Pesch Beate B Johnen Georg G Brüning Thomas T Bickeböller Heike H Gomolka Maria M

International archives of occupational and environmental health 20180703 8

<h4>Purpose</h4>Radon is a risk factor for lung cancer and uranium miners are more exposed than the general population. A genome-wide interaction analysis was carried out to identify genomic loci, genes or gene sets that modify the susceptibility to lung cancer given occupational exposure to the radioactive gas radon.<h4>Methods</h4>Samples from 28 studies provided by the International Lung Cancer Consortium were pooled with samples of former uranium miners collected by the German Federal Office ...[more]

PMID: 29971594

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Project description:BackgroundHigh radon exposure is a risk factor for squamous cell carcinoma, a major lung cancer histology observed in former uranium miners. Radon exposure can cause oxidative stress, leading to pulmonary inflammation. Interleukin-6 (IL-6) is a pro-carcinogenic inflammatory cytokine that plays a pivotal role in lung cancer development.ObjectivesWe assessed whether single nucleotide polymorphisms (SNPs) in the IL6 promoter are associated with lung cancer in former uranium miners with high occupational exposure to radon gas.MethodsGenetic associations were assessed in a case-control study of former uranium miners (242 cases and 336 controls). A replication study was performed using data from the Gene Environment Association Studies (GENEVA) Genome Wide Association Study (GWAS) of Lung Cancer and Smoking. Functional relevance of the SNPs was characterized using in vitro approaches.ResultsWe found that rs1800797 was associated with squamous cell carcinoma in miners and with a shorter time between the midpoint of the period of substantial exposure and diagnosis among the cases. Furthermore, rs1800797 was also associated with lung cancer among never smokers in the GENEVA dataset. Functional studies identified that the risk allele was associated with increased basal IL-6 mRNA level and greater promoter activity. Furthermore, fibroblasts with the risk allele showed greater induction of IL-6 secretion by hydrogen peroxide or benzo[a]pyrene diolepoxide treatments.ConclusionsAn IL6 promoter variant was associated with lung cancer in uranium miners and never smokers in two external study populations. The associations are strongly supported by the functional relevance that the IL6 promoter SNP affects basal expression and carcinogen-induced IL-6 secretion.CitationLeng S, Thomas CL, Snider AM, Picchi MA, Chen W, Willis DG, Carr TG, Krzeminski J, Desai D, Shantu A, Lin Y, Jacobson MR, Belinsky SA. 2016. Radon exposure, IL-6 promoter variants, and lung squamous cell carcinoma in former uranium miners. Environ Health Perspect 124:445-451; http://dx.doi.org/10.1289/ehp.1409437.

Project description:BackgroundDespite reductions in exposure for workers and the general public, radon remains a leading cause of lung cancer. Prior studies of underground miners depended heavily upon information on deaths among miners employed in the early years of mine operations when exposures were high and tended to be poorly estimated.ObjectivesTo strengthen the basis for radiation protection, we report on the follow-up of workers employed in the later periods of mine operations for whom we have more accurate exposure information and for whom exposures tended to be accrued at intensities that are more comparable to contemporary settings.MethodsWe conducted a pooled analysis of cohort studies of lung cancer mortality among 57,873 male uranium miners in Canada, Czech Republic, France, Germany, and the United States, who were first employed in 1960 or later (thereby excluding miners employed during the periods of highest exposure and focusing on miners who tend to have higher quality assessments of radon progeny exposures). We derived estimates of excess relative rate per 100 working level months (ERR/100 WLM) for mortality from lung cancer.ResultsThe analysis included 1.9 million person-years of observation and 1,217 deaths due to lung cancer. The relative rate of lung cancer increased in a linear fashion with cumulative exposure to radon progeny (ERR/100 WLM=1.33; 95% CI: 0.89, 1.88). The association was modified by attained age, age at exposure, and annual exposure rate; for attained ages <55 y, the ERR/100 WLM was 8.38 (95% CI: 3.30, 18.99) among miners who were exposed at ≥35 years of age and at annual exposure rates of <0.5 working levels. This association decreased with older attained ages, younger ages at exposure, and higher exposure rates.DiscussionEstimates of association between radon progeny exposure and lung cancer mortality among relatively contemporary miners are coherent with estimates used to inform current protection guidelines. https://doi.org/10.1289/EHP10669.

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Genetic modifiers of radon-induced lung cancer risk: a genome-wide interaction study in former uranium miners.

Publications

Genetic modifiers of radon-induced lung cancer risk: a genome-wide interaction study in former uranium miners.

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